Vascular dysfunction accompanies the active disease process of atherosclerosis and is determined in large part by endothelial cell dysfunction (Ludmer et al., 1986; Nabel et al., 1994; Treasure et al., 1995; and Wilkinson et al., 2002). This impairment is due, in part, to the generation of oxygen radicals, such as superoxide anion (02), peroxynitrite or hydrogen peroxide (H202), which create a highly oxidative environment. Oxygen radicals are produced by the endothelium and other vascular cells under the influence of cytokines as a major causative component of the atherosclerotic process.
Proteins and lipids in this environment are altered in a variety of ways. One class of biological compounds that are most vulnerable to oxidation is the group of polyunsaturated fatty acids that exist in cell membranes and in circulating lipoproteins. This reaction generates a series of reactive aldehydes that form covalent bonds with other molecules in the immediate environment. One of the most common reactions appears to be that with the epsilon amino group of the lysine side chains, which exist as components of nearby proteins. This generates a new surface epitope on the protein, which is immunogenic. The occurrence of circulating antibodies to malondialdehyde (MDA)-lysine side groups on proteins seems to be ubiquitous among humans and is commonly found in animals as well (Avogaro et al., 1988; Yla-Herttuala et al., 1989; Holvoet et al., 1995; and Yla-Herttuala et al., 1994).
Arteriosclerosis means hardening of the arteries and is a generic term for three patterns of vascular disease that have in common thickening and loss of elasticity of arterial walls. The dominant pattern is atherosclerosis, characterized by the formation of intimal fibrous plaques that often have a central core rich in lipid. The second morphologic form of atherosclerosis is characterized by calcified deposits in medium-sized muscular arteries in persons older than 50 years. These lesions typically do not encroach on the vessel lumen. Arteries affected may also develop atherosclerosis. The third type affects small arteries and arterioles and is termed arteriolosclerosis. This involves thickening of vessel walls with luminal narrowing that may induce downstream ischemic injury. Arteriolosclerosis is most often associated with hypertension and diabetes.
Atherosclerosis is characterized by intimal lesions called atheromas or fibro-fatty plaques that protrude into the lumen, weaken the underlying media, and undergo a series of complications. Atherosclerosis primarily affects elastic arteries (e.g., aorta, carotid and iliac arteries) and large and medium-sized muscular arteries (e.g., coronary and popliteal arteries). The disease often begins in childhood, but symptoms are not usually evident until middle age or later when the arterial lesions precipitate organ injury. Although any organ or tissue in the body may be so involved, symptomatic atherosclerosis disease is most often localized to the arteries supplying the heart, brain, kidneys, lower extremities, and small intestine. Myocardial infarction (heart attack), cerebral infarction (stroke), and aortic aneurysms are the major consequences of this disease.
The key processes in atherosclerosis are intimal thickening and lipid accumulation, producing the characteristic atheromatous plaques. The atheromatous plaque is the basic lesion consisting of a raised focal plaque within the intima, having a core of lipid (mainly cholesterol and cholesterol esters) and a covering fibrous cap. Also called fibrous, fibro-fatty, lipid, or fibrolipid plaques, atheromatous plaques appear white to whitish yellow and impinge on the lumen of the artery. They vary in size from approximately 0.3 to 1.5 cm in diameter but sometimes coalesce to form larger masses. The distribution of atherosclerotic plaques in humans is characteristic. The abdominal aorta is usually much more involved than the thoracic aorta, and aortic lesions tend to be much more prominent around the origins (ostia) of its major branches. Atherosclerotic plaques have three principal components: (1) cells, including smooth muscle cells, macrophages, and other leukocytes; (2) connective tissue extracellular matrix, including collagen, elastic fibers, and proteglycans; and (3) intracellular and extracellular lipid deposits. Fatty streaks are also often observed in the lumen of blood vessels and may be precursors of atheromatous plaques. The streaks begin as multiple yellow, flat spots (fatty dots) less than 1 mm in diameter that coalesce into elongated streaks, 1 cm long or longer. Fatty streaks are composed of lipid-filled foam cells with T lymphocytes and extracellular lipid present in smaller amounts than in plaques. Fatty streaks appear in the aortas of some children younger than 1 year of age and all children older than 10 years, regardless of geography, race, sex, or environment. Coronary fatty streaks are less common than aortic but begin to form in adolescence, and they occur at the same anatomic sites that are later prone to develop plaques. Although fatty streaks may be precursors of plaques, not all fatty streaks are destined to become fibrous plaques or more advanced lesions.
Despite the information known regarding the pathophysiology of atherosclerosis, in clinical trials of efficacious treatments, there is little available to the clinician to determine early in the course of treatment which patients have altered endothelial pathophysiology. No test or assay is currently available that can be used for adjusting treatments to achieve a “normal result” that predicts the expected improvement in long-term outcome.
Therefore, a heretofore-unaddressed need exists in the art to address the aforementioned deficiencies and inadequacies.